The Requirement Of SEPT2 And SEPT7 For Migration And Invasion In Human Breast Cancer Via MEK/ERK Activation

Objective: Septins constitute a family of highly conserved GTP-binding proteins from yeast to human,and by far 14 members have been identified in human genome.Septins are categorized as the fourth cytoskeletal proteins and can assemble into higher-order cytoskeletal structures including filaments,bundles and rings by heteromeric complex formation.Basic elements for septin core structure have been described by forming non-polar SEPT2/6/7 hexamer.An emerging body of studies reveals that septins maintain a conserved role in cytokinesis and have also been implicated in a variety of other cellular functions such as chromosome segregation,DNA repair,cell polarization,migration and apoptosis.In addition,septins are reported to be tightly associated with human physiological and pathological events,including bacterial infection,Alzheimer disease,Parkinson disease,and male infertility.Currently,numerous studies have indicated that alterations of septin proteins,by mutation or expression changes,strongly link with tumorigenesis.Therefore,septins might be critical proteins in the development of certain cancers and merit deeply exploration to further disclose the mechanisms whereby they function.Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide.Despite improvement in overall survival of breast cancer patients,drug resistance remains a huge challenge for clinical therapy and crucial for disease recurrence and progression.Therefore,the existing situation necessitates an extensive search for novel bio-molecules that may be acted as safe and effective drug targets.Cytoskeleton proteins are being developed as a new class of therapeutic targets for breast cancer.The researches indicate that septins can modulate microtubule-based breast cancer chemotherapy by their guidance towards microtubule and actin cytoskeleton dynamics,which have been quite well described in epithelial cells and neuron cells.Given the importance of septins as non-conventional cytoskeletons in the regulation of cytokinesis and mitosis in various human cancers,we hypothesized septins are likely to be involved in the pathogenesis of breast cancer by modulating malignant phenotypes of cancer cells.Moreover,the basic information concerning the role of septin family and representative members in affecting breast cancer cell biology is at present largely unknown.Herein,this study aimed at determining whether septin proteins could influence breast cancer cell biological behavior,including cell proliferation,migration and invasion,and uncovering its underlying mechanism.Method:(1)The detection of the effects of FCF on proliferation,single cell colony formation,apoptosis and invasion in BC cell lines.(2)Detection of the expressions of SEPT2 and SEPT7 in different breast cancer cell lines and the location of SEPT2 and SEPT7 in BC cells.(3)Detection of the effects of knockdown for SEPT2 and SEPT7 on BC cell proliferation,apoptosis,migration and invasion.(4)Detection of the effects of SEPT2 and SEPT7 overexpression on proliferation,cell cycle,migration and invasion in MDA-MB-231 cells.(5)Preliminary explore the cell signaling pathways which Septin engaged in.Results:(1)Pharmaceutical inhibition(FCF:the inhibitor of septin family)of global septin dynamics would greatly suppress proliferation,migration and invasiveness in breast cancer cell lines.(2)In comparison to the high invasive breast cancer cell lines(MCF7 and MDA-MB-231 cell),the SEPT2 and SEPT7 have a higher expression in the low invasive breast cancer cell(T47D)or normal breast cell(MCF10A);SEPT2 and SEPT7 have a co-localization in cleavage ring of telophase cells.(3)SEPT2/7 depletion can inhibit the cellular proliferation,migration,invasion and elevate early and total apoptotic rates in breast cancer cells.(4)SEPT2/7 overexpression can improve cellular proliferation,migration and invasion but don’t have significant influence on cell cycle.(5)SEPT2 and SEPT7 are required for MEK/ERK activationConclusions: The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation.